Gastric acid secretion inhibiting composition

ABSTRACT

An oral pharmaceutical dosage form comprises pharmacologically effective amounts of an acid-susceptible proton pump inhibitor and an H2 receptor antagonist in combination with at least on pharmacologically acceptable excipient which causes a delayed release and/or an extended release of the proton pump inhibitor. The H2 receptor antagonist is included in the dosage form in such a way that it is rapidly released after administration. This dosage form is suitable for the treatment of conditions associated with an excessive secretion of gastric acid and provides a suitable combination of a rapid onset and a long-lasting duration of the effect. The invention also relates to a method for manufacturing such a dosage form and to a method for the treatment of conditions associated with the secretion of gastric acid.

FIELD OF THE INVENTION

The present invention relates to a gastric acid secretion inhibitingcomposition, to a method for its manufacture and to its use in treatingconditions which are related to the secretion of gastric acid.

BACKGROUND OF THE INVENTION

During the latest decades, much progression has been made in thesuppression of acid secretion, an integral part of the treatment ofdyspeptic disorders such as gastro-oesophageal reflux disease (GORD),duodenal and gastric ulcers and non-ulcer dyspepsia. Although thepathophysiology of these disorders is not identical, the inhibition ofgastric acid secretion is pivotal to healing organic lesions,alleviating symptoms of discomfort and improving the quality of life.Moreover, acid-related damage may underlie the progression to cancersand other late complications of these conditions. Inhibition of acidsecretion is also a cornerstone in the treatment regimens aiming foreradication of Helicobacter pylori infection.

Dyspepsia (acid dyspepsia) is a common disorder. Heartburn is a symptomof dyspepsia. It is estimated that 44% of Americans have heartburn atleast once monthly but that only about 25% of them are seeing the doctorbecause of their dyspepsia problem. Symptoms associated with dyspepsiaare for instance upper abdominal pain/discomfort and heartburn,indigestion, “sour” stomach, and gastro-esophageal reflux.

Dyspepsia is a multi-factorial disease and may be associated withorganic pathology such as duodenal ulcer, gastric ulcer, esophagitis,Barrett's esophagus or gastro-duodenal inflammation (e.g., Helicobacterpylori infection). Dyspepsia also includes conditions where no organicpathology can be found, e.g., non-ulcer dyspepsia (NUD) or functionaldyspepsia.

Dyspepsia can be controlled by administration of medicines that raisethe pH in the stomach. Therapeutic agents effective in the treatment ofdyspepsia include gastric acid suppressing agents, such as histamine H2receptor antagonists (in the following called H2 receptor antagonists),acid susceptible proton pump inhibitors, antacids/alginates,anticholinergics and prokinetic. agents. They can be distinguished bytheir mechanism of action, safety profile, and pharmacokinetics. Thestomach pathogen Helicobacter pylori has been associated with dyspepsia,gastro-duodenal ulcer disease and stomach cancer. The treatment of H.pylori infection usually comprises the administration of a combinationof acid secretion suppressing agents and one or two antibiotic agents.

The therapeutic effect on dyspepsia-related discomfort and organiclesions when inhibiting acid production by administration of acidsecretion-inhibiting drugs is related to the degree of acid inhibitionas well as to the onset and duration of action of the particular drug.The majority of patients who have symptomatic acid reflux disease have anormal esophageal mucosa or only a mild degree of oesophagitis.Treatment to relieve symptoms as they occur may be the best way tomanage these patients, to whom the speed of symptom relief is of primaryimportance.

Antacid agents, that is, acid-neutralizing agents, and alginates are thefirst therapeutic choice in the treatment of mild heartburn. They have aextremely short duration of action but are seen as inexpensive and safe.Antacid agents work locally through a neutralization of gastric acid.Alginates provide some mechanical protection against reflux of gastricacid into the esophagus. The main advantages of antacid agents andalginates are that they provide fast relief of symptoms. The maindisadvantage of antacid agents and alginates is their extremely shortduration of action, and dosing has to be repeated frequently to keep thepatients free of symptoms, further that antacids often do not providesymptom resolution, i.e. complete relief of symptoms. Moreover, theseagents are not at all useful in the treatment of acid induced organiclesions, GORD or Helicobacter pylori infection.

Several classes of compounds are known which affect the secretion ofgastric acid. Among them, acid susceptible proton pump inhibitors, suchas the substituted benzimidazoles omeprazole, lanzoprazole, rabeprazoleand pantoprazole and histamine H2 receptor antagonists, such ascimetidine, ranitidine and famotidine are the most prominent ones. H2receptor and acid susceptible proton pump inhibitors are widelyprescribed for reducing gastric acid secretion systemically.

The design of acid suppression therapy requires a detailed understandingof the mechanisms behind the secretion of hydrogen ions, namely theparietal cell and hydrogen-potassium adenosine triphosphate(H⁺,K⁺-ATPase) so that these mechanisms can be effectively targeted withpharmacological intervention. Three key factors have been identified inorder to achieve an effective pharmacological treatment of acid relateddisorders (Dig Dis Sci 1995 vol 40: 24S-49S. Optimizing acid suppressionfor treatment of acid-related diseases.):

1) Time to onset of action, i.e. the inhibition of acid secretion shouldoccur as rapidly as possible.

2) Degree of acid inhibition, i.e. the intragastric pH should be keptwell above 4.

3) Duration of action, i.e. the inhibition of acid.secretion shouldremain virtually complete during 24 hours on the first dose and remaincomplete during the course of treatment.

All of these factors must be considered when deciding how to optimizesaid suppressive therapy. However, several aspects of the parietal cellphysiology and the pharmacology/biochemistry of existing pharmaceuticalshave to date prevented the achievement of this goal.

Central to the acid secretory mechanism are the parietal cells of thestomach. These cells secrete hydtogen ions into the gastric lumen underthe control of neurocrine, paracrine and endocrine pathways. One of themajor paracrine factors is histamine released by theenterochromaffine-like (ECL) cells. The histamine released from the ECLcells stimulates parietal cells to acid secretion via histamin-2(H2)receptors located on the cell surface. Engagement of these receptorsresults in cyclic adenosine-3,5-monophosphate (cAMP) elevation and cAMPbinding to the regulatory subunit. A variety of proteins will bephosphorylated, all of which will be relevant to activation ofsecretion. The molecular dissection of this intracellular pathway is farfrom complete, however, the action of cAMP includes translocation ofH⁺,K⁺-ATPase into the secretory canaliculus and activation of the KCLtransporters, i.e. put the parietal cell into a secretory state.

The first attempts of decreasing acid secretion targeted the paracrinepathway, namely the histamine H2 receptor activation-induced stimulationof acid secretion. Accordingly, the first class of acid inhibitors wasthe H2 receptor antagonists (H2 blockers), including compounds such ascimetidine, ranitidine, famotidine and nizatidine. Their mode of actionis to antagonize the effects of histamine, i.e. to inhibit therecruitment of proton pumps to the secretory canaliculus and reduce theactivity of KCL transport. This will put the parietal cells into anon-secretory state and thereby reduce the output of hydrogen ions (DigDis Sci 1995, vol 40:3S-23S. Pharmacological aspects of acid secretion).

However, phenomena of acid rebound and tolerance are major drawbacks tothe use of these drugs in treating acid related diseases. There is anapproximately 50% loss in acid reduction capacity during repeateddosing, which severely restricts the use of this class of drug in thetreatment of, for example, GORD (Aliment Pharmacol Ther 1990, vol 4:29-46. Tolerance during 29 days of conventional dosing with cimetidine,nizatidine, famotidine or ranitidine). Moreover, these agents are not atall useful in the treatment of Helicobacter pylori infection, atreatment dependent on an effective and sustained reduction of acidsecretion.

Current treatment of acid related disorders is focused on a more directtarget, the H⁺,K⁺-ATPase (“proton pump”) of the active parietal cell.These cells constitute the final acid sources—the acid secretorycanaliculus and the acid pump itself. Therefore, drugs designed toinhibit acid secretion at this level show a greater efficacy andspecificity. Because proton pump inhibitors (PPIs) act at a stepdownstream of the parietal cell stimulus, tolerance does not occur withthe use of these compounds, in contrast to the H2 receptor antagonists.Moreover, these drugs hit the final target to which all other pathwaysconverge, the H⁺,K⁺APPase in the acid space or canaliculus of thestimulated parietal cell.

Individual PPIs are similar with respect to their general structure,which consists of a substituted pyridylmethylsulfinyl benzimidazole. PKavalues for these compounds vary from 4.0 to 5.0. All PPIs share the samepharmacological mechanism that is essentially the same: their pKarestricts accumulation of the compound to acid spaces, such as that inthe parietal cell.. PPI accumulation in the canaliculus of the parietalcell is followed by an acid-dependent activation step whereby the PPI isconverted to sulphenic acid or sulphenamides. Formation of thesereactive intermediates allows for binding to cysteine residues withinthe exposed luminal surface of the H⁺, K⁺-ATPase. The enzyme isfunctionally inactivated via the production of covalent disulphidebonds. The inhibition of H⁺, K⁺-ATPase by PPIs thus results in arelatively stable inhibition of the enzyme, as de novo synthesis of theenzyme is required to reverse the inhibition. These mechanisms of actionis described in Dig Dis Sci 1995, vol 40:3S-23S. Pharmacological aspectsof acid secretion.

One of the fundamental characteristics of the PPls is that they are onlyfunctional in active parietal cells, i.e. the cells have to be in asecretory state. The rason for this is three-fold. Firstly, in mostparietal cells, the acid space (canaliculus) has a pH of about 1.0. Atthis pH, the pKa values of PPIs allow them to accumulate in the parietalcell 1000- to 10,000-fold. However, at higher pH, for example 3, thisaccumulation decreases by two orders of magnitude, i.e. to 10- to100-fold. Thus, the weak base characteristics of the PPIs allow them toaccumulate only when acid is being formed by the parietal cell. Thisbecomes important when administering PPIs during conditions when theparietal cell is put into a non-secretory state. Secondly, theconversion of PPI to sulphenic acid or sulphenamide is an acid-dependentprocess. Thirdly, the H⁺,K⁺-ATPase has to be activated, i.e. the enzymehas to be inserted into the membrane of the secretory canaliculus, whereits cysteine residues can be reached by the sulphenamides(Pharmacotherapy 1997 vol 17:22-37. Proton pump inhibitors and acidrelated diseases; Drugs 1998 vol 56:307-335. Proton pump inhibitors:pharmacology and rationale for use in gastrointestinal disorders; Ann NYAcad Sci 1997 vol 834:65-76 Structural aspects of the gastric H⁺,K⁺-ATPase; Annu Rev Pharmacol Toxicol 1995 vol 35:277-305. Thepharmacolology of the gastric acid pump).

These characteristics of the pharmiacology/biochemistry of the PPIs willprofoundly affect the pharmacodynamics of this class of compounds. Onone hand, these drugs require an active enzyme for inhibition and somepumps are not active while the drug is present in the blood. On theother hand, the PPIs exhibit a relatively short plasma half-life of 60minutes, and new pumps are synthesized at a rate of 25% per 24 hours.

These facts point to the therapeutic dilemma of PPIs at present. As thecompounds are accumulated and converted in the acidic space of theparietal cell, only those pumps which are secreting acid will beinhibited. Since the cell has a reserve of inactive pumps and is in theprocess of synthesizing new pumps, many pumps destined to be activewithin the next 24 hours will not be inhibited by the first dose.However, the following day, when PPI is given again, new pumps have beenrecruited and can be inhibited, and the pumps inhibited 24 hourspreviously have not been replenished entirely. Therefore, the responseto PPIs is cumulative, reaching a steady state and therapeutic acidinhibition first after at least three consecutive days of treatment.

Thus, the current concept regarding PPIs mechanisms of action is theneed for active pumps to mediate their effects. In the resting state,parietal cells produce no acid and the pumps are inactive. Theinhibition of acid production by PPIs occurs when these pumps are in theactive state, via accumulation in the parietal cell, such thatsubsequent activation of the drug results in an inhibition of the pump(Eur J of Gastroentereol Hepatol 2001 vol 13:S35-S41. Improving onPPI-based therapy of GORD)

In summary, neither class of anti-secretory drugs available today attainthe goal for acid control stated above, i.e. of a rapid onset of action,potent inhibition of acid secretion and a sustained duration of actionduring the course of treatment. This goal is of the utmost importancefor the clinical outcome of treatment, as the therapeutic effect isrelated to the onset, degree and duration of action, i.e. how quickly,how much and for how long the pH is raised in the stomach.

Various combinations of antacid and/or mucosa-protecting agents withagents that reduce acid secretion have been disclosed to be useful intreating dyspepsia.

WO 95/017080 describes a composition for use in the treatment of forinstance heartburn comprising an H2 receptor antagonist, such asfamotidine, and an alginate and optionally simethicone (an activatedpolysiloxane).

EP 338861 A describes a solid pharmaceutical preparation consisting ofan antacid and excipients which is proposed to be used in combinationwith an acid-susceptible proton pump inhibitor or any other substanceinhibiting gastric acid secretion. There is no suggestion to combinethese substances in a fixed unit dosage form.

U.S. Pat. No. 5,244,670 A describes an ingestible pharmaceuticalcomposition comprising a substance selected from the group consisting ofantacid agents, acid secretion-prevention agents, bismuth-containingagents and their mixtures, and 3-(1-menthoxy)-propane-1,2-diol which ispresent to provide a cooling sensation to the throat.

WO 97/25066 discloses a pharmaceutical formulation comprising acombination of an acid-susceptible proton pump inhibitor or an H2receptor antagonist and one or more antacid agents or alginates.

Neither acid-susceptible proton pump inhibitors nor H2 receptorantagonists, alone or in combination with antacids and/or alginates,provide fully satisfactory quick and lasting relief to patients, to whomthe speed of symptom relief is of primary importance but who also desireto be free of symptoms for a longer period of time. Thus, none of thesolid pharmaceutical preparations for per-oral administration reportedto date, satisfies the basic requirements; rapid onset of acid secretioninhibition, potent reduction of acid secretion and a sustainedinhibition of acid secretion.

Furthermore, the use of proton pump inhibitors has a serious shortcomingregarding chemical stability:

The substances are extremely acid-labile, which has made specialformulations necessary. Normally, the substances are protected in vivoby the application of a gastric acid-resistant coating (enteric coating)over the active substance. As such coatings in themselves are acidic(release hydrogen ions), it has been found that it is also necessary toprovide some sort of protection in vitro, i.e. when the product isstored.

This protection in vitro may be arranged such as is described in U.S.Pat. No. 6,183,776 B1 (Depui et al.), where an alkaline-reactingsubstance is added together with the proton pump inhibitor, and asupplementary protective coating (sub-coat) is applied just under thegastric acid-resistant coating.

Another approach is disclosed in WO 00/78284 (U.S. Pat. No. 5,225,202),where the gastric acid-resistant coating is neutralized such that itshows no acid reaction during storage. After swallowing, the hydrogenions present in the stomach will acidify the coating and thus recreatethe acid-protecting properties of the coating in situ.

It has now been found that both the problem regarding rapid and longlasting relief of symptoms as well as the chemical instability problemof acid succeptible proton pump inhibitors may be solved by the presentinvention.

OBJECTS OF THE INVENTION

It is an object of the invention to provide a medicine which providesquick and lasting relief to a patient suffering from conditions relatedto gastric acid secretion.

It is another object of the invention to provide a method for treating apatient suffering from conditions related to gastric acid secretionwhich provides quick and lasting relief.

Further objects of the invention will be evident from the followingshort description of the invention, a preferred embodiment thereof, andthe appended claims.

SUMMARY OF THE INVENTION

The present invention relates to a solid pharmaceutical dosage form fororal administration, which is characterized in that it comprises a H2receptor antagonist formulated for a rapid release and a PPI which isformulated for an extended release. In the present dosage form, therapidly released H2 receptor antagonist will be rapidly absorbed andinhibit acid secretion by the mechanisms described above. The PPIformulated for delayed and/or extended release will maintain a maximalacid suppression already after the first dose and maintain a maximalacid suppression during the course of treatment.

Acid-susceptible proton pump inhibitors are acid-activated prodrugs thatcovalently inhibit the gastric H+,K+-ATPase, the proton-transportingenzyme involved in the production of hydrochloric acid in the stomach.The action of gastric H+,K+-ATPase represents the final step in thesequence of events resulting in secretion of hydrochloric acid by theparietal cell. Thus inhibition of this enzyme is the most effective andspecific means of controlling acid secretion regardless of the nature ofthe stimulus to secretion. As would be expected with such a mechanism ofaction, proton pump inhibitors such as omeprazole has been shown toinhibit both basal and stimulated acid secretion. Omeprazole is a weakbase which accumulates in the acidic milieu of the secretory membrane ofthe parietal cell where it undergoes rearrangement in acid to its activesulphenamide form which subsequently reacts with sulfhydryl groups ofthe acid pump.

In gastric mucosa, the acid-susceptible proton pump is situated in theapical membrane and in the tubovesicles bordering the secretorycanaliculus of the parietal cell. Thus, after a single dose, omeprazolerapidly accumulates in the acidic compartment of the secretory membranewhere its active sulphenamide form irreversible binds to theH+,K+-ATPase. The H+,K+-ATPase situated in the tubovesicles will howevernot be exposed for activated omeprazole. A major portion of synthesizedH+,K+-ATPase will thus escape blockade after a single omeprazole dose.This may explain why the maximal acid-inhibitory effect of omeprazole isreached only after about five days of treatment.

H2 receptor antagonists competitively inhibit the action of histamine onall H2 receptors, mainly on the surface of the parietal cells. Attherapeutic doses, these agents are capable not only of decreasing bothbasal and nocturnal acid secretion, but also secretion stimulated byfood, histamine, insulin and pentagastrin. A single dose of an H2receptor antagonist results in maximal acid inhibitory effect alreadywithin 2 hours after intake. Furthermore, the acid inhibitory effectobtained with high doses of an H2 receptor antagonist is built uprapidly but has a tendency to fade substantially during the following2-7 days, while the acid inhibitory effect of omeprazole gradually isbuilt up during the same period of time.

The present invention is based on the unexpected finding that an almostcomplete inhibition of acid secretion is achieved by the first dose ofan acid susceptible proton pump inhibitor administered as an extendedrelease formulation. Furthermore, as only activated proton pumpssecreting acid during the time PPI is present in the plasma is expectedto be inhibited, it was surprisingly found that a sustained inhibitionof acid secretion could be achieved while the parietal cells is put intoa non-secretory state by means of the rapidly released H2 receptorantagonist.

Thus, according to the invention, there is provided an oralpharmaceutical dosage form comprising pharmacologically effectiveamounts of an acid-susceptible proton pump inhibitor or a salt thereof,and an H2 receptor antagonist or a salt thereof, and a pharmaceuticallyacceptable excipients resulting in delayed and/or extended release ofthe proton pump inhibitor. The terms “proton pump inhibitor” and “H2receptor antagonist” include their isomers, such as enantiomers ofproton pump inhibitors, as well as pharmaceutically acceptable salts ofsuch isomers.

The invention is especially suitable for “on demand” treatment ofgastro-esophageal reflux complaints e.g. heartburn, where potent acidreduction is needed for a shorter period of time and where a rapid onsetof action is most important and a maximal acid reduction is to prefer.The maximal acid inhibitory effect would be able to be maintained duringa 7 days period by the elimination of the “fade-off” phenomenon seenafter H2-blocker given alone. This will be important in order to reducethe time for the treatment of stomach ulcers, acid-related lesions inthe esophagus and Helicobacterp) ori eradication.

To overcome the previously mentioned problems associated with the protonpump inhibitors, the invention comprises three parts:

1) By formulating the proton pump inhibitor into a composition whichreleases active substance with a delayed effect (delayed release) and/orwith a prolonged effect (extended release), a composition is obtainedwhich acts completely opposite to what has been desired up to nowregarding a rapid onset of the effect. However, a new type of protectionfor these acid-labile pharmaceutical substances is provided.

This type of release-controlled composition is well-known to thoseskilled in the art and has a number of different designations.

In the present specification, the expression “extended release” is usedas a synonym to “prolonged release” and “sustained release”.Irrespective of which expression is used, the common function is thatthe release of the active substance is retarded and extended over alonger time. This is normally obtained by either providing a core ofactive substance with a coating or membrane of suitable auxiliary agentswhich control the release, or by incorporating the active substance in amatrix of suitable auxiliary agents.

The expression “delayed release” is used in the present specification todescribe compositions which do not release active substance immediately.The start of the release is thus displaced to the small intestine orlarge intestine. This type of composition is normally obtained byproviding a core of active substance with a coating or membrane which ischanged during the transport in the gastro-intestinal tract by thechanges in pH encountered by the composition, or by a change in thecoating as a function of the time when the composition is in contactwith body fluids. The present type of composition is not to be confusedwith gastric acid-resistant compositions (“non-enteric release) whichare only intended to protect the composition from hydrogen ions or,alternatively, to protect the patient from a deleterious effect of themedical compound on the stomach.

The expressions “controlled release” and “modified release” may also beused to describe this part of the invention, but they constitute morecollective designations which do not specifically describe the presenttype of release mechanisms.

All these types of designations, principles for formulation and suitableauxiliary agents are well-known to those skilled in the art, andreference is here made to the manual “Pharmaceutics. The Science ofDosage Form Design”, 1^(st) edition; Ed. M. E. Aulton, ChurchillLivingstone, Edinburgh 1988, which is hereby incorporated by reference.Reference is especially made to pages 289-305.

It is clear that the basic composition hereby provided may be combinedwith further additions of auxiliary agents. Thus, for example, theproton pump inhibitor may be blended with an alkaline reacting substanceto neutralize the small amount of hydrogen ions which may pass throughthe membrane or matrix structures during the passage through thestomach. This measure is not strictly necessary, but leads to a moreperfect composition. In the same manner, a gastric acid-resistantcoating may be provided on the exterior side of the membrane or matrixpart of the composition. In a further embodiment, these two formulationmeasures may be used at the same time.

2) The problem of a too slow onset of the increase in pH is notobviously solved by further retarding or time-expanding the release.However, it has now turned out that it is possible to administer an H2receptor antagonist having a rapid onset of effect (obtained through arapid release), without compromise the onset of action of thesubsequently released acid susceptible proton pump inhibitor. This wasunexpected since an important feature of PPIs is the need for activepumps to mediate their effects. During influence of an H2 receptorantagonist, the parietal cells are put into a resting state. In theresting state, parietal cells produce no acid and the pumps areinactive. The inhibition of acid production by PPIs occurs only whenthese pumps are in the active state, via accumulation in the parietalcells, such that subsequent activation of the drug results in aninhibition of the pump. Thus, the present invention provides a novelpharmacological composition utilizing the rapid inhibition of acidsecretion from a histamine 2 receptor antagonist without offsetting theeffect of the concomitantly administered PPI.

3) From the current knowledge of PPI mode of action and the biochemistryof H⁺, K⁺-ATPase, it is not obvious how to achieve maximal inhibition ofacid secretion with the first dose of a PPI (wide supra).

However, it has now turned out that expanding the time during which PPIis released results in an unexpected efficient first dose inhibition ofacid secretion. By extend the time for PPI present in the blood, newlysynthesized pumps will be continuously inactivated. This was unexpected,as following the initial inhibition of the pump, the pH in the secretoryspace would rise and the drug will depronate and diffuse back out of thecanaliculus. Furthermore, the second clearly essential step in the thePPIs action , the acid-catalysed conversion into the activesulphenamide, would not take place.

The combination described here may be obtained in two ways. Firstly, aseparate dose having a delayed/extended release of the proton pumpinhibitor may be administered concurrently with a separate dose of theH2 receptor antagonist. Alternatively, these two substances havingdifferent release profiles may be combined into the same preparation. Anumber of examples will illustrate how this is suitably arranged.

Thus, the present invention provides a sustained acid suppressionalready after the first dose. This cannot be attained by the productsproposed by the prior art:

H2 blockers are only active during the first 6-8 hours.

H2 blockers+ antacids give a rapid onset, but are only active for 6-8hours

PPIs give no action at all after the first dose.

PPIs+ antacids are active for about one hour through the antacid effect.

PPI enantiomer will not reach its full potential after the first dose.

PPI slow release alone will give an effect first after 5-6 hours

Thus, the present invention provides an important improvement over theformulations of the prior art. This improved effect is considered to bedue to the unexpected clinical/physiological effect attained through heunique preparation of the invention, i.e. the delayed/extended effect ofthe PPI in combination with the rapid release of the H2 blocker.

Some patent publications are known which disclose combinations of aproton pump inhibitor and compositions for delayed release, andreference may here be made to U.S. Pat. No. 6,132,768, U.S. Pat. No.6,274,173 B1 and DE 199 25 710 A1. These references are directed toincreasing the stability of proton pump inhibitors against degradationand discoloration caused by hydrogen ions. However, they do not teachanything about any combination of a proton pump inhibitor and an H2receptor antagonist and the unexpected advantages attained thereby.

Furthermore, a gastric acid secretion inhibiting composition is knownfrom the international patent application PCT/SE02/00757. Thiscomposition comprises a combination of an acid-susceptible proton pumpinhibitor and an H2 receptor antagonist, but no mention is made of theexcipient system of the present invention and its unexpected advantages.

According to the invention, there is provided an oral dosage formcomprising an H2 receptor antagonist in an amount effective to reducethe acidity in the stomach after administration and an acid-susceptibleproton pump inhibitor in an amount effective to sustain the low acidityeffected by the H2 receptor antagonist over an extended period of time.It is preferred for the pharmacologically effective amounts to beamounts capable of raising gastric pH to above 3 within 2 hours fromadministration and to keep it above 3 for at least 4 hours, preferablyfor at least 8 hours. It is more preferred for said pharmacologicallyeffective amounts to be amounts capable of raising gastric pH to above 4within two hours after administration and to keep it above 4 for atleast 8 hours, more preferred for at least 16 hours.

According to a first preferred aspect of the invention the H2 receptorantagonist is provided in an amount which is capable of providing atleast 80% of maximal reduction, more preferred at least 95% of maximalreduction, of the acidity in the stomach within about two hours.“Maximal reduction” is the reduction of acidity which can be maximallyobtained by administering an H2 receptor antagonist alone intherapeutically accepted amounts, that is, in amounts in which suchdrugs are administered in the art. The term “H2 receptor antagonist(s)”as used herein includes all agents that substantially inhibit or blockthe secretion of gastric acid by binding to histamine type 2 receptorsin the stomach. At therapeutic doses such H2 receptor antagonists arecapable not only of decreasing basal and nocturnal acid secretion, butalso secretion stimulated by food, histamine, insulin and pentagastrin.Exemplary H2 receptor antagonists according to the invention arecimetidine, ranitidine, nizatidine and famotidine which are normallyused in the form of their pharmacologically. acceptable salts, inparticular hydrochlorides The dosage form of the invention preferablycomprises from 1 mg to 800 mg of H2 receptor antagonist or salt thereof,more preferred from 5 mg to 400 mg.

According to a second preferred aspect of the invention theacid-susceptible proton inhibitor is provided in an amount which iscapable of maintaining the low acidity effected by the histamine H2antagonist over at least 6 hours. Acid-susceptible proton pumpinhibitors are rapidly taking market share from H2 receptor antagonists.The term “acid-susceptible proton pump inhibitor(s)”, as used herein,comprises benzimidazole derivatives having substantial H+,K+-ATPaseinhibiting activity, in particular or leprazole, pantoprazole,lanzoprazole, rabeprazole, pariprazole, leminoprazole and theirpharmaceutically acceptable salts and enantiomers and salts ofenantiomers, but include also the other compounds disclosed on pages7-11 of WO 97/25066 which are hereby incorporated by reference as wellas those disclosed in EP 005 129 A1, EP 174 726 A1, EP 166 287 A1, GB 2163 747, WO 90/06925, WO91/19711, WO91/19712, WO94/27988, WO95/01977.

Thus the dosage form of the invention comprises preferably from 1 mg to100 mg, more preferred from 5 mg to 50 mg, per single dose of anacid-susceptible proton pump inhibitor or a salt thereof. Theacid-susceptible proton pump inhibitor or salt thereof is separated fromthe H2 receptor antagonist by he formulation principle, where only theproton pump inhibitor is coated by the membrane or incorporated in amatrix for the purpose of delayed and/or extended release.

According to a third preferred aspect of the invention the H2 receptorantagonist formulated for rapid release and the acid-susceptible protonpump inhibitor formulated for delayed and/or extended release need notto be comprised by the same pharmaceutical composition but may beadministered separately but within a narrow time interval, such as atime interval of one hour, in particular a time interval of 30 min, mostpreferred a time interval of 10 min. Thus is disclosed a correspondingdose regimen for separate but joint administration of anacid-susceptible proton pump inhibitor and an H2 receptor antagonist totreat a.condition related to gastric acid secretion.

The oral dosage form of the invention thus comprises an acid-susceptibleproton pump inhibitor formulated for delayed and/or extended release, anH2 receptor antagonist formulated for rapid release and, optionally, agastric acid-suppressing agent and/or an alginate. Preferably, thedosage form of the invention comprises from 100 mg to 1000 mg of antacidagent and/or alginate. The antacid agent of the invention comprises. oneor several of aluminum hydroxide, calcium carbonate, magnesiumcarbonate, basic magnesium carbonate, magnesium hydroxide, magnesiumoxide and sodium hydrogen carbonate.

Due to the fact that acid-susceptible proton pump inhibitors aregenerally sensitive to acid (acid-susceptible proton pump inhibitors)they need to be administered in a form which protects them fromdegradation in the stomach to make them pass into the small intestinewhere they are absorbed. In this new invention, this is largely solvedby. the use of excipients for delayed and/or extended release whichoffers protection, without the known disadvantage of enteric coatinglayers (i.e. liberation of hydrogen ions, that will increase thedegradation rate of the proton pump inhibitors). H2 receptorantagonists, on the other hand, can be administered without suchprotection. According to a further preferred aspect of the invention,compositions can be adapted to suit the purpose of the present inventionare among those disclosed in WO 97/25066.

The oral dosage forms of WO 97/25066 comprise an acid-susceptible protonpump inhibitor in an amount similar or identical to that used in thecomposition of the present invention, and one or several antacid agentsand/or alginate(s). The adaptation of the compositions of WO 97/25066essentially consists firstly, in adding the membrane—or matrix system tothe part of the formulation that contains the proton pump inhibitor andsecondly, in substituting a pharmacologically effective amount of an H2receptor antagonist for a portion of or the entire amount of the antacidagent(s) and/or alginate.

According to the invention, there is provided an oral, multiple-unittableted dosage form comprising an acid-susceptible proton pumpinhibitor in individually delayed/extended release coated unitsoptionally coated with an enteric coating layer in combination with anH2 receptor antagonist in the form of a powder or granules.compressedinto a tablet. The enteric coating layer(s) covering the individualunits of the acid-susceptible proton pump inhibitor has properties suchthat the compression of the units into a tablet does not significantlyaffect the acid resistance of the individually coated units.Furthermore, the multiple unit tableted dosage form provides a goodstability to the active substances during long-term storage.

According to the invention, there is also provided a multiple-unittableted dosage form, which is divisible and easy to handle. Such amultiple-unit tableted dosage form comprises delayed/extended releasecoated pellets of an acid-susceptible proton pump inhibitor optionallycoated with an enteric coating layer compacted with a powdery H2receptor antagonist. This dosage forn may also contain effervescentcomponents for making it disintegrate rapidly when.put into water. ThepH of the aqueous phase must then be made slightly acidic to preventdissolution of any present enteric layer. This dosage form can be givento patients with swallowing disorders and in pediatrics. Such asuspension of dispersed units/pellets of appropriate size can be usedfor oral administration and also for feeding through a naso-gastrictube.

According to the invention, there is also provided a tablet preparationcomprising an acid-susceptible proton pump inhibitor in admixture withtablet excipients forming a tablet core which is coated with excipientsfor delayed and/or extended release, and a separate layer surroundingthe tablet core. The surrounding layer comprises an H2 receptorantagonist in admixture with a pharmaceutical excipient. Optionally aseparating layer is applied on the tablet core before the core iscovered with the coating. A further option is than to also apply, on topof the other coats, an enteric coating layer. Alternatively, theprepared tablet is sectioned in separate layers, each one comprisingdifferent active substances. One of the layers, preferably the.innermost layer (core), comprises the acid-susceptible proton pumpinhibitor in the form of coated pellets in admixture with pharmaceuticalexcipients and the other layer(s) comprise(s) the histamineH2-antagonist(s), respectively in admixture with pharmaceuticalexcipient(s). Optionally the two layers are separated by a separatinglayer to prevent tacking between the two layers. The coated core,comprising the acid-susceptible proton pump inhibitor may alsoadvantageously be coated with an enteric layer by following, forinstance, procedures disclosed in WO 00/78284, which is incorporatedherein by reference.

According to the invention, the acid-susceptible proton pump inhibitorin the form of coated pellets may be mixed with histamineH2-antagonist(s) and optionally pharmaceutical excipient(s) to beadministered in a sachet intended for oral administration afterdispersion in a slightly acidic aqueous solution.

It is thus preferred for the dosage form of the invention to comprisethe acid-susceptible proton pump inhibitor or a salt thereof protectedby a coating layer for delayed and/or extended release and optionallyalso an enteric coating layer. Preferably the dosage form of theinvention comprises two concentric layers optionally separated by one ormore separating layer(s), one layer comprising said acid-susceptibleproton pump inhibitor or salt thereof, the .other layer comprising saidH2 receptor antagonist or salt thereof.

The inner layer comprises the acid-susceptible proton pump inhibitor ora salt thereof and the outer layer comprises the H2 receptor antagonistor a salt thereof. According to a preferred aspect the outer layercomprises a disintegrant. The oral dosage form of the invention may takedifferent shapes, such as a tablet, a capsule, a divided powder/pelletformulation, and the like.

Further, the proton pump-containing part of the formulations have abovebeen described to exert their delayed and/or extended release effect byapplying coatings to a core material of the proton pump inhibitor.However, another approach is instead to exchange the coating layer(s),i.e. the membrane system to a matrix system. The excipients are thenchosen to form a lipid or water insoluble matrix. The function of thematrix is then to exert an extended release of the proton pumpinhibitor.

According to the invention, there is also disclosed a method for themanufacture of an oral tableted dosage form comprising amounts of anacid-susceptible proton pump inhibitor or a salt thereof and an H2receptor antagonist or a salt thereof pharmacologically effective intreating a condition related to dyspepsia, the method comprising forminga first layer comprising said acid-susceptible proton pump inhibitor orsalt. thereof, a coating of excipents for delayed and/or extendedrelease and optionally an enteric coating surrounding said first layer,and a second layer comprising said H2 receptor antagonist or saltthereof surrounding said first. layer and said coating. Also disclosedis a method for the manufacture of an oral dosage form comprisingamounts of an acid-susceptible proton pump inhibitor or a salt thereofand an H2 receptor antagonist or a salt thereof pharmacologicallyeffective in treating a condition related to dyspepsia, the methodcomprising forming pellets comprising said acid-susceptible proton pumpinhibitor or salt thereof, covering said pellets with the abovementioned coatings, and mixing said pellets with a carrier comprisingsaid H2 receptor antagonist or salt thereof, the carrier optionallycomprising a disintegrant. The aforementioned methods of the inventionfurther comprise a final tablet forming step, optionally followed by afilm-covering step.

Another method for the manufacture of the oral dosage form of theinvention comprises filling a capsule capable of disintegrating ingastrointestinal fluids to release its contents with the mixturecomprising coated proton pump inhibitor pellets and a H2 receptorantagonist in powdery or granular form.

Regarding the methods for the manufacture, the proton pump-containingpart of the formulations have above been described to exert theirdelayed and/or extended release effect by applying coatings to a corematerial of the proton pump inhibitor. However, another approach isinstead to exchange the coating layer(s), i.e. the membrane system to amatrix system. The excipients are then chosen to form a lipid or waterinsoluble matrix. The function of the matrix is then to exert anextended release of the proton pump inhibitor.

The use of the pharmaceutical dosage form of the invention is howevernot restricted to provide quick and lasting relief to a patientsuffering from conditions related to gastric acid secretion. The rapidonset of inhibition of gastric acid secretion combined with themaintenance of inhibition as long as desired (by repeated administrationof a composition comprising an acid-susceptible proton pump inhibitor,preferably by repeated administration of the composition of theinvention) can be expected to have a positive effect on the healing ofgastric- and duodenal- ulcers and esophagitis for which the maintenanceof intra-gastric pH above 4 for a maximal duration is acknowledged(Huang J Q and Hunt R H, pH, healing rate and symptom relief in patientswith GERD, Yale J Biol Med 1999, 72:181-94). The composition of theinvention thus is also preferred for maintaining gastric pH above 4 forextended periods of time, such as 4 hours and more. The dosage form ofthe invention can also be used, in association with one or moreantibiotic agent(s), for the eradication of Helicobacter pylori.

According to the invention, there is also disclosed a method of treatingdisorders associated with gastric acid secretion, the method comprisingthe administration of the dosage form of the invention or theconcomitant administration of two. separate oral dosage forms, onecomprising a pharmacologically effective amount of an acid-susceptibleproton pump inhibitor or a salt thereof, formulated for delayed and/orextended release, the other comprising a pharmacologically effectiveamount of an H2 receptor antagonist or a salt thereof, formulated forrapid release.

Furthermore, according to the invention, there is disclosed a method oftreating an infection by Helicobacter pylori, comprising theadministration of the dosage form of the invention or the concomitantadministration of two separate oral dosage forms, one comprising apharmacologically effective amount of an-acid-susceptible protoninhibitor or a salt thereof, the other comprising a pharmacologicallyeffective amount of an H2 receptor antagonist or a salt thereof, inassociation with the administration of one or more antibiotic agent(s)effective against H. pylon.

It is preferred for the aforementioned methods of treatment according tothe invention to comprise a dose regimen capable of maintaining gastricpH above 4 for at least 95% of the time period starting at 2 hours fromthe administration of the first dose and extending until. 6 hours fromthe administration of the last dose, in particular a regimen wherein thetime period is one week or more, preferably two weeks or more, even morepreferred four weeks or more. Also preferred in this context is a doseregimen capable of maintaining gastric pH above 3 for at least 95% ofthe time period starting at 2 hours from the administration of the firstdose and extending until 6 hours from the administration of the lastdose, in particular for four weeks or more.

The invention will now be described in greater detail by reference to anumber of preferred but not limiting embodiments illustrated in adrawing.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1-4 of the drawings are schematic cross sections illustrating:

-   -   FIG. 1 a multiple unit tableted dosage form comprising an        acid-susceptible proton pump inhibitor in the form of delayed        and/or extended release coated pellets in admixture with an        H2-receptor antagonist dispersed in a pharmaceutical carrier;    -   FIG. 2 a tableted dosage form consisting of two halves, one of        which comprises delayed and/or extended release coating-covered        pellets of an acid-susceptible proton pump inhibitor in        admixture with excipients whereas the other comprises an H2        receptor antagonist in admixture with excipients;    -   FIG. 3 a multiple-layered tableted dosage form comprising an        acid-susceptible proton pump inhibitor in a core surrounded by a        delayed and/or extended release coating layer and a layer        containing an H2 receptor antagonist dispersed in a        pharmaceutical carrier surrounding the core;    -   FIG. 4 a capsule dosage form containing an acid-susceptible        proton pump inhibitor in delayed and/or extended release        coating-covered pellets in admixture with an H2 receptor        antagonist and pharmaceutical excipients;

DESCRIPTION OF PREFERRED EMBODIMENTS

Multiple-unit tableted dosage form:

The multiple-unit tableted dosage form of the invention illustrated inFIG. 1 consists of a tablet body 1 optionally covered by a film layer 3and small pellets 2 distributed at random in the tablet body 1. Thepellets 2 contain an acid-susceptible proton pump inhibitor in form ofthe racemate, an alkaline salt or one of its enantiomers. The individualunits 2 (small beads, granules or pellets) containing theacid-susceptible proton pump inhibitor and optionally containingalkaline substances, are coated with a layer(s) possessing delayedrelease and/or extended release and optionally an additional entericcoating layer. The coated units, 2 are then mixed with the H2 receptorantagonist and conventional tablet excipients forming, in combination,the tablet body 1. The H2 receptor antagonist and tablet excipients maybe dry mixed or wet mixed into granules. The mixture of coated layeredunits, H2 receptor antagonist and excipients are compressed into themultiple unit tableted dosage forms. By the expression “individualunits” is meant small beads, granules or pellets, in the followingreferred to as proton pump inhibitor pellets. In yet another embodimentof the invention, also the H2 receptor antagonist is coated onto the“individual units”. Then the H2 receptor antagonist must be positionedin a pheripheral position in relation to the coating layers for delayedand/or extended release and enteric release, in order to be rapidlyreleased in the gastro-intestinal tract. In compressing the mixture intotablets, care must be taken not to significantly affect the acidresistance of the coated pellets. In regard of the core material forcoating layered pellets comprising an acid-susceptible proton pumpinhibitor reference is made to WO 97/25066, page 13, second to lastparagraph, to page 15, end of second paragraph, which are herebyincorporated by reference. In regard of the coating layer(s) excertingthe delayed and/or extended release reference is made to U.S. Pat. No.6,274,173, which are hereby incorporated as reference. Reference is alsomade to “Pharmaceutics. The Science of Dosage Form Design.”, 1^(st)edition; Ed. M. E. Aulton, Churchill Livingstone, Edinburgh 1988.Reference is then especially made to pages 289-305. In regard of theenteric coating layer(s) reference is made to WO 97/25066, page 15,second to last paragraph, to page 18, end of second paragraph, which arehereby incorporated by reference. The acid-susceptible proton pumpinhibitor pellets covered with layers for delayed and/or extendedrelease and optionally an enteric coating layer(s) may be furthercovered with one or more over-coating layers. In regard of suchover-coating layer(s) reference is made to WO 97/25066, page 18, lastparagraph, to page 19, end of first paragraph, which are herebyincorporated by reference. The H2 receptor antagonist is dry mixed withinactive excipients such as filler, binders, disintegrants, and otherpharmaceutically acceptable additives. The mixture is wet massed with agranulation liquid. The wet mass is dried preferably to a loss on dryingof less than 3% by weight. Then the dry mass is milled to a suitablesize for granules, preferably smaller than 1 mm. Suitable inactiveexcipients are, for instance, mannitol, corn starch, potato starch, lowsubstituted hydroxypropyl cellulose, microcrystalline cellulose andcrosslinked polyvinylpyrrolidone. The dry mixture comprising the H2receptor antagonist may be mixed with a suitable granulation liquidcomprising, for instance, hydroxypropylcellulose orpolyvinyl-pyrrolidone dissolved in water or alcohol or their mixtures.Alternatively the H2 receptor antagonist is dry mixed withpharmaceutically acceptable excipients (see supra). As mentioned above,in another embodiment of the invention the H2 receptor antagonist can becoated onto the small units, 2, rather than mixed with excipients toform the tablet body, 1. Irrespective of how the H2 receptor antagonistis incorporated it should possess a rapid release.

Multi-unit tablets:

The coated layered pellets comprising an acid-susceptible proton pumpinhibitor are mixed with the H2 receptor antagonist granules or with theprepared dry mixture comprising the H2 receptor antagonist. The mixtureis admixed with lubricant(s) and compressed into a multiple unittableted dosage form. Suitable lubricants for the tableting process are,for instance, sodium stearyl fumarate, magnesium stearate and talc. Thecompressed tablets are optionally covered with film-forming agent(s) toobtain a smooth surface. Such a coating layer may further compriseadditives such as anti-tacking agents, colorants and pigments or otheradditives.

The fraction of coated pellets preferably constitutes less than 60% byweight of the total tablet weight. The preferred multiple-unit tableformulation thus consists of delayed and/or extended release coatedlayered pellets optionally coated with an enteric coating layer,comprising the acid-susceptible proton pump inhibitor, optionally inadmixture with alkaline reacting compound(s), compressed into tabletswith the prepared H2 receptor antagonist/excipient(s) mixture. Theoptional enteric coating layer(s) make(s) the pellets of the dosage forminsoluble in acidic media but disintegrating/ dissolving in near neutralto alkaline media, such as the gastric fluid present in the proximalpart of the small intestine where the dissolution and uptake of theacid-susceptible proton pump inhibitor is desired. The delayed releasecoating layer, will then start to release the acid susceptible protonpump inhibitor after a certain time period in the gastrointestinal tractor at a certain pH, reached at some position in the intestine or colon.The extended release coating layer will extend the release of the protonpump inhibitor in order to result in drug absorption during severalhours. The delayed and/or extended release coated proton pump inhibitorpellets may also be covered with an overcoating layer before beingformulated into tablets, and they may also contain one or moreseparating layer(s) in between the core material and the other layers.

Process for making multi-unit tablets:

The process for the manufacture of this dosage form represents a furtheraspect of the invention. After formulating the pellets by dry mixing(ordered mixture), spray coating or layering of the acid-susceptibleproton pump inhibitor onto seeds, or by extrusion/spheronization orgranulation, the pellets are first optionally covered with theseparating layer(s) and then covered with the delayed and/or extendedrelease layer(s) and then optionally covered with the enteric coatinglayer(s). The coating is carried out as described above and in theaccompanying examples. The preparation of the H2 receptor antagonistmixture is also described in the examples. Optionally the H2 receptorantagonist can be coated onto the already existing layers comprisingdelayed and/or extended release layer(s) and enteric coating layer.

The coated pellets, with or without an overcoat, are mixed with theprepared H2 receptor antagonist granules or dry powder, tabletexcipients and other pharmaceutically acceptable additives andcompressed into tablets. Alternatively, the coated proton pump inhibitorpellets may be covered by a second layer containing the H2 receptorantagonist as described in the following examples. Furthermore, asillustrated in FIG. 2, the coated pellets 4 may be intimately mixed withexcipients 5 and pre-compressed whereafler the H2 receptor antagonistpreparation 7 is added and the entire tablet mass finally compressedinto a tablet, optionally with film-forming agent(s) 6 to obtain asmooth surface. As a further alternative illustrated in FIG. 3, theacid-susceptible proton pump inhibitor in the form of a powder may bemixed with. tablet excipients and compressed into a tablet 8 which isoptionally covered with a separating layer and thereafter covered withdelayed and/or extended release coating 9. Optionally, an entericcoating layer is applied. The thus produced tablet core is subsequentlypress-coated with the H2 receptor antagonist preparation 10. Finally thetable may be covered with a tablet coat 11 to obtain a smooth surface.

It is also possible to fill the acid-susceptible proton pump inhibitorin form of coated layered pellets in a sachet together with H2 receptorantagonist and optionally mixed with excipients.

FIG. 4 illustrates a hard gelatin capsule 16 filled with theuncompressed core material 14, IS of the embodiment of FIG. 1.

In the examples given (FIG. 1, 2, 3, and 4) the terms coating, coatinglayer or layer have been used. These terms are exchangeable and alsoidentical to the term membrane. Irrespective of the nomenclature theyhave in common that they correspond to more or less continuous phases ofexcipient materials applied by e.g. spraying onto a core material. Dueto the nature of the processing these membranes are relatively thin withregard to thickness.

Suitable excipient materials for forming coatings layers (or membranes)for delayed and/or extended release are non-polymeric-orpolymeric.materials such as calcium phosphate, ethyl cellulose,methacrylate copolymer, polyamide, polyethylene, polyvinyl alcohol orpolyvinyl acetate.

Further, the proton pump-containing part of the formulations (2 in FIG.1, 4 in FIG. 2, 8 in FIG. 3 and 15 in FIG. 4) have above been describedto exert their delayed and/or extended release effect by applyingcoatings to a core material of the proton pump inhibitor. However,another approach is instead to exchange the coating layer(s), i.e. themembrane system to a matrix system. The excipients are then chosen toform a lipid or water insoluble matrix. The function of the matrix isthen to exert an extended release of the proton pump inhibitor. Suitablematrix forming. excipients are non-polymeric-or polymeric materials suchas calcium phosphate, ethyl cellulose, methacrylate copolymer,polyamide, polyethylene or polyvinyl acetate, camauba wax, cetylalcohol, hydrogenated vegetable oils, microcrystalline waxes, mono- andtriglycerides, polyethylene glycol or polyethylene glycol monostearateand most preferably camauba wax, cetyl alcohol, hydrogenated vegetableoils, microcrystalline waxes, mono- and triglycerides, polyethyleneglycol or polyethylene glycol monostearate. In order to obtain anoptimal release rate, hydrophilic, pore-forming excipients can beoptionally added. Suitable hydrophilic, pore forming materials arealginates, carbopol, gelatin, hydroxypropyl cellulose, hydroxypropylmetylcellulose or metylcellulose.

In general, the methods of WO 97/25066 for making oral pharmaceuticaldosage forms comprising an acid susceptible proton pump inhibitor and anantacid agent or alginate can be adapted to suit the purpose of thepresent invention by firstly, adding the membrane or matrix system tothe part of the formulation that contains the proton pump inhibitor andsecondly, by substituting part or the entire amount of antacid agent oralginate by a pharmacologically effective amount of an H2 receptorantagonist, the remainder of the antacid agent or alginate (ifsubstitution is not 1:1 by weight) being omitted or substituted byexcipients like microcrystalline cellulose, silica, lactose, mannitol,ant the like.

USE OF THE DOSAGE FORMS ACCORDING TO THE INVENTION.

The dosage forms according to the invention are especially advantageousin the treatment of dyspepsia and other gastrointestinal disordersrelated to the production of gastric acid to provide quick and lastingrelief from symptoms. The dosage forms are administered once or severaltimes a day. The typical daily dose of the acid-susceptible proton pumpinhibitor and the H2 receptor antagonist will depend. on various factorssuch as individual requirements of patients, the mode of administration,and the particular condition to be treated. In general each dosage formwill comprise from 1 mg to 100 mg of acid-susceptible proton pumpinhibitor and from 1 to 800 mg of the H2 receptor antagonist. Preferablyeach dosage form will comprise from 5 to 50 mg of the acid-susceptibleproton pump inhibitor and from 5 to 200 mg of the H2 receptorantagonist. The multiple unit tablet preparation is also suitable fordispersion in water, which has been made slightly acidic by the additionof citric acid.

EXAMPLE 1

Multiple-unit tableted dosage form comprising magnesium omeprazole andcimetidine hydrochloride; batch size 400 tablets. For omeprazole Mg-saltpellet production (core material, separating layer, enteric coatinglayer and over-coating layer, see WO 97/25066, p. 22-23 under respectiveheadings), see WO 97/25066, first two 20 paragraphs, all of which ishereby incorporated by reference. The extended release layer is applied,by a coating process, in between the separation layer and the entericcoating layer, in accordance with what is described in patent U.S. Pat.No. 6,274,173, Example 1-4, using ethyl cellulose or polyvinyl acetateas extended release forming excipients, the information under which ishereby incorporated as reference. Tablets Prepared pellets comprisingomeprazole Mg-salt 31.3 g Microcrystalline cellulose 300.0 g Cimetidinehydrochloride 40.0 g Potato starch 50.0 g Water 200.0 g PVP crosslinked38.0 g Sodium stearyl fumarate 4.6 g

A small amount of the potato starch is dissolved in purified hot waterto form the granulation liquid. Cimetidine hydrochloride, the rest ofpotato starch and microcrystalline cellulose are dry mixed. Thegranulation liquid is added to the dry mixture and the mass is wetmixed. The wet mass is dried in an oven at 50° C. The preparedgranulation is milled through sieve 1 mm in an oscillating millequipment. The coated. pellets. with an over-coating layer, the preparedH2 receptor antagonist granules, cross-linked polyvinylpyrrolidone andsodium stearyl fumarate are mixed and compressed into tablets using atableting machine equipped with oval punches. The amount of omeprazolein each tablet is approx. 10 mg and the amount of cimetidinehydrochloride. is approx. 100 mg.

By a slight modification this multiple-unit tablet form can be made tocomprise an antacid agent (instead of microcrystalline cellulose, 300mg: microcrystalline cellulose, 100 g; calcium carbonate, 100 mg;magnesium oxide, 100 mg; all other constituents, except water, in theamounts given above).

EXAMPLE 2

Three-layered tableted dosage form. The tablet comprises theacid-susceptible proton pump inhibitor omeprazole, a separating layerand a core layer comprising cimetidine hydrochloride. Batch size 1000tablets. First tablet layer Cimetidine hydrochloride 200.0 gMicrocrystalline cellulose 250.0 g PVP crosslinked 13.0 g Sodium stearylfumarate 3.8 g Separating layer Microcrystalline cellulose 80.0 g Secondtablet layer Coated pellets comprising omeprazole magnesium salt (sameas in EXAMPLE 1) 78.3 g Microcrystalline cellulose 174.0 g PVPcrosslinked 26.0 g Sodium stearyl fumarate 1.4 g

The constituents of the first tablet layer are dry mixed andpre-compressed as a first layer in a tableting machine equipped withoval punches. Microcrystalline cellulose is filled on the top of thefirst layer to form a separating layer to the next layer. Theconstituents of the second tablet layer are dry mixed and filled on topof the separating layer. The three layers are compressed into athree-layer tablet,. which may be coated by a tablet coating layer. Theamount of omeprazole is approx. 10 mg and that ofcimetidine.hydrochloride approx. 200 mg per tablet.

EXAMPLE 3

Capsule dosage form. No. 1 hard gelatin capsules (16) (FIG. 5; volume0.48 ml) were filled with extended release-coated omeprazole pellets(15) containing 20 mg omeprazole (as prepared in EXAMPLE 1) and a drymixture 14 of commercially available famotidine 20 mg and closed.

EXAMPLE 4

Divided powder/pellet formulation. Extended release pellets containing15 mg lansoprazole. (as prepared in analogy with EXAMPLE 1) and thefamotidine preparation were dry mixed with citric acid. Single doseportions thereof containing 10 mg each of lansoprazole and famotidinehydrochloride and 200 mg powderous citric acid were dry packed inplastic laminate. The composition is intended to be poured into 20 ml ofwater, stirred for a short time, and swallowed.

EXAMPLE 5

Multiple-unit capsule dosage form. The capsule comprises magnesiumomeprazole and famotidine hydrochloride. For extended release coatinglayer, see U.S. Pat. No. 6,274,173, Example 1-4, the information underwhich is hereby incorporated as reference. For enteric coating layer andover-coating layer, see WO 97/25066, page 22-23 under respectiveheadings, the information under which is hereby incorporated byreference.

Magnesium omeprazole is mixed with microcrystalline cellulose spheres toan ordered mixture. The ordered mixture is coated with an extendedrelease layer, consisting of polyvinyl acetate, micronised lactose,propylene glycol and ammonia (25%) in a fluid bed apparatus. Theseextended release pellets were the coated with an enteric coating layerconsisting of methacrylic acid copolymer, mono- and diglycerides,triethyl citrate and polysorbate in a fluid bed apparatus. The extendedrelease/enteric coated ordered units is then over-coated with a watersuspension containing famotidine hydrochloride, hydroxypropylmethylcellulose and magnesium stearate in a fluid bed apparatus. The extendedrelease/enteric coated ordered mixture with an over-coating layer wasfilled into hard gelatin capsules. The amount of omeprazole is approx.10 mg and that of famotidine hydrochloride approx. 20 mg per capsule.

EXAMPLE 6

Multiple-unit tableted dosage form. The tablet comprises magnesiumomeprazole and cimetidine hydrochloride. Magnesium omeprazole is mixedwith mannitol granules to an ordered mixture which is coated with bothan extended release coating layer and an enteric coating layer asdescribed in EXAMPLE 5. Cimetidine hydrochloride is granulated asdescribed in EXAMPLE 1. The coated ordered mixture comprising magnesiumomeprazole, the cimetidine granules and excipients- are dry mixed andcompressed into tablets. The amount of omeprazole in each tablet isapprox. 10 mg and that of cimetidine is approx. 100 mg.

EXAMPLE 7

Multiple-unit tableted dosage form for instant release of H2 receptorantagonist and colon extended release of proton pump inhibitor. Thetablet comprises magnesium omeprazole and cimetidine hydrochloride.

Core Material

Omeprazole magnesium salt 120 g

Sugar sphere seeds 150 g

Hydroxypropyl methylcellulose 18 g

Polysorbate 80 2.4 g

Water purified 562 g

Suspension layering was performed in a fluid bed apparatus. Omeprazolemagnesium salt was sprayed onto sugar sphere seeds from a watersuspension containing the dissolved binder and polysorbate 80. The sizeof sugar sphere seeds were in the range of 0.25 to 0.35 mm.

Extended Release Layer

Core material (acc. to above) 200 g

Eudragit® RTM 100 g

Hydroxypropyl cellulose 10 g

Delayed Release Layer

Pellets covered with extended release layer (acc. to above) 250 g

Eudragit® FS 30 D 100 g

The prepared core material was covered with both an extended releaselayer and a delayed release layer in a fluid bed apparatus withcommercially available water-based suspensions, Eudragit® RTM andEudragit® FS 30 D, respectively.

Enteric Coating Layer

Pellets covered with both a delayed release and extended release layer(acc. to above) 250 g

Methacrylic acid copolymer (30% suspension) 333.7 g

Triethyl citrate 30 g

Mono- and diglycerides (NF) 5 g

Polysorbate 80 0.5 g

Water purified 196 g

The enteric coating layer consisting of methacrylic acid copolymer,mono-and diglycerides, triethyl citrate and polysorbate was sprayed ontothe pellets covered with extended/delayed release layers in a fluid bedapparatus. The enteric coating layered pellets were classified bysieving.

Tablets

Prepared pellets comprising omeprazole Mg-salt 63.7 g

Cimetidine hydrochloride 65.0 g

Calcium carbonate 123.9 g

Magnesium hydroxide 123.9 g

Potato starch 52.2 g

Water purified 435 g

Microcrystalline cellulose 175 g

Polyvidone crosslinked 50.0 g

Sodium stearyl fumarate 6.0 g

A small amount of the potato starch was dissolved in hot purified waterto form the granulation liquid. Cimetidine hydrochloride, calciumcarbonate, magnesium hydroxide and potato starch were dry-mixed. Thegranulation liquid was added to the dry mixture and the mass waswet-mixed.

The wet mass was dried in a steamoven at 40 DEG C. The preparedgranulation was milled through sieve 1 mm in an oscillating millequipment.

The multiple coated layered pellets, prepared granules, polyvidonecrosslinked, microcrystalline cellulose and sodium stearyl fumarate weremixed and compressed into tablets using a tableting machine equippedwith 9.times.20 mm oval punches. The amount of omeprazole in each tabletwas approx. 20 mg and the same amount was used for cimetidinehydrochloride.

Tablet hardness was measured to 30N.

Optionally the obtained tablets were covered with a tablet coatinglayer.

1. An oral pharmaceutical dosage form comprising pharmacologicallyeffective amounts of an acid-susceptible proton pump inhibitor or a saltthereof and an H2 receptor antagonist or a salt thereof, and at leastone pharmaceutically acceptable excipient(s) which results in a delayedrelease and/or extended release of the acid-susceptible proton pumpinhibitor or the salt thereof, and said H2 receptor antagonist or thesalt thereof is included in such a way that it is rapidly released fromsaid dosage form.
 2. The dosage form of claim 1, wherein theacid-susceptible proton pump inhibitor is selected from lansoprazole,omeprazole, pantoprazole, rabeprazole, pariprazole, leminoprazole, theirpharmaceutically acceptable salts, enantiomers and salts of enantiomers.3. The dosage form of claim 1, comprising from 1 mg to 100 mg of theacid-susceptible proton pump inhibitor or a salt thereof per singledose.
 4. The dosage form of claim 1, wherein the H2 receptor antagonistis selected from cimetidine, ranitidine, nizatidine and famotidine,their pharmaceutically acceptable salts, isomers and salts of isomers.5. The dosage form of claim 4, comprising from 1 mg to 800 mg of H2receptor antagonist or salt thereof.
 6. The dosage form of claim 1wherein the excipient(s) exerts the release controlling activity in theform of a membrane applied onto a core comprising the acid-susceptibleproton pump inhibitor or a salt thereof, or in the form of a matrixsystem where the acid-susceptible proton pump inhibitor or a saltthereof is incorporated into the excipent(s).
 7. The dosage form ofclaim 1 wherein the H2 receptor antagonist or a salt thereof forms anouter layer applied onto a core comprising the acid-susceptible protonpump inhibitor or a salt thereof and excipients, wherein the core formsa matrix or membrane system, capable of delayed and/or extended releaseof the acid-susceptible proton pump inhibitor or a salt thereof.
 8. Thedosage form of claim 1, wherein the excipient(s) used to form themembrane or matrix are inert or lipid.
 9. The dosage form of claim 8,wherein the inert excipient(s) are non-polymeric-or polymeric materialssuch as calcium phosphate, ethyl cellulose, methacrylate copolymer,polyamide, polyethylene, polyvinyl alcohol or polyvinyl acetate.
 10. Thedosage form of claim 8, wherein the lipid excipient(s) arenon-polymeric-or polymeric materials such as carnauba wax, cetylalcohol, hydrogenated vegetable oils, microcrystalline waxes, mono- andtriglycerides, polyethylene glycol or polyethylene glycol monostearate.11. The dosage form of claim 9, wherein additional hydrophilicexcipent(s) are used, such as alginates, carbopol, gelatin,hydroxypropyl cellulose, hydroxypropyl metylcellulose or metylcellulose.12. The dosage form of claim 6, wherein an enteric coating layer isapplied onto the membrane or matrix system and, optionally, a layerseparating the enteric coating from the membrane or matrix system. 13.The dosage form of claim 6, wherein an alkaline-reacting substance isadmixed together with the acid-susceptible proton pump inhibitor or thesalt thereof.
 14. The dosage form of claims 1, wherein saidpharmacologically effective amounts are amounts capable to raise gastricpH to above 4 within two hours after administration and to keep it above4 for at least 4 hours.
 15. The dosage form of claim 14, wherein saidamounts are capable to keep gastric pH above 4 for at least 8 hours. 16.The dosage form of claim 14, wherein said pharmacologically effectiveamounts are amounts capable to raise gastric pH to above 3 within 2hours from administration and to keep it above 3 for at least 4 hours.17. The dosage form of claim 16, wherein said amounts are amountscapable to keep gastric pH above 3 for at least 8 hours.
 18. The dosageform of claim 1, comprising from 100 mg to 1000 mg of antacid agentand/or alginate.
 19. The dosage form of claim 18, wherein the antacidagent comprises one or several of aluminum hydroxide, calcium carbonate,magnesium carbonate, basic magnesium carbonate, magnesium hydroxide,magnesium oxide, sodium hydrogen carbonate.
 20. The dosage form of claim1, wherein the acid-susceptible proton pump inhibitor or a salt thereofand excipients, together forming a membrane or matrix system, arepresent in the form of a multiple-unit system consisting of a pluralityof small units, consisting of pellets, granules or beads.
 21. The dosageform of claim 20, wherein the small units in the multiple-unit systemalso contain an outer layer of a H2 receptor antagonist or a saltthereof.
 22. The dosage form of claim 20, wherein the small units aredispersed in a H2 receptor antagonist or a salt thereof, optionallyadmixed with pharmaceutically acceptable excipients, such asdisintegrant(s).
 23. The dosage form of claim 1, comprising two halves,one of which comprising an acid-susceptible proton pump inhibitor or asalt thereof in admixture with excipients capable of forming a matrix ormembrane system and the other half comprising an H2 receptor antagonistor a salt thereof, optionally admixed with pharmaceutically acceptableexcipients, such as disintegrant(s).
 24. A capsule according to claim 1.25. A divided powder/pellet formulation according to claim
 1. 26. Atablet according to claim
 1. 27. The tablet of claim 26, beingdivisible.
 28. The tablet of claim 26, being dispersible in water. 29.The tablet of claim 28, comprising a disintegrant.
 30. A method for themanufacture of an oral pharmaceutical dosage form comprisingpharmacologically effective amounts of an acid-susceptible proton pumpinhibitor or a salt thereof and an H2 receptor antagonist or a saltthereof, and at least one pharmaceutically acceptable excipient whichresults in a delayed release and/or extended release of theacid-susceptible proton pump inhibitor or the salt thereof, and said H2receptor antagonist or the salt thereof is included in such a way thatit is rapidly released from said dosage form, said method comprisingforming a first layer comprising said acid-susceptible proton pumpinhibitor or salt thereof, and forming a coating thereon of said atleast one excipient, and forming a second layer comprising said H2receptor antagonist or salt thereof surrounding said first layer andsaid coating, and subsequently formulating the combined product of saidfirst layer, said coating and said second layer into an oralpharmaceutical dosage form.
 31. A method according to claim 30, whereinsaid acid-susceptible proton pump inhibitor is enclosed in said leastone excipient, said excipient forming a lipid or water-insoluble matrix.32. A method according to claim 30, wherein said first layer is formedto pellets, which are subsequently coated with said at least oneexcipient and are subsequently mixed with a carrier comprising said H2receptor antagonist or salt thereof.
 33. A method according to claim 32,wherein said carrier comprises a pharmacological disintegrant.
 34. Amethod according to claim 30, wherein said combined product isformulated into a tablet.
 35. A method according to claim 30, whereinsaid combined product is formulated into a capsule capable ofdisintegrating in gastro-intestinal fluids.
 36. A method according toclaim 30, wherein said oral pharmaceutical dosage form is provided withan enteric coating.
 37. A method according to claim 30, wherein saidacid-susceptible proton pump inhibitor is selected from the groupconsisting of lansoprazole, omeprazole, pantoprazole, rabeprazole,pariprazole, lemiprazole and their pharmaceutically acceptable salts,enantiomers and salts of enantiomers.
 38. A method according to claim30, wherein said H2 receptor antagonist is selected from the groupconsisting of cimetidine, ranitidine, nizatidine, famotidine and theirpharmaceutically acceptable salts, isomers and salts of isomers.
 39. Useof an oral pharmaceutical dosage form according to claim 1, for themanufacture of a medicament for the treatment of conditions associatedwith the secretion of gastric acid.
 40. Use of an oral pharmaceuticaldosage form according to claim 1, in association with one or moreantibiotic agents for the eradication of Helicobacter pylori.
 41. Amethod of treating a condition associated with the secretion of gastricacid, wherein an oral pharmaceutical dosage form according to claim 1 isadministered in a therapeutically effective amount to an individualhuman or animal afflicted with said condition.
 42. A method for treatingan infection by Helicobacter pylori, wherein an oral pharmaceuticaldosage form according to claim 1 in association with one or moreantibiotic agents effective against H. pylori is administered in atherapeutically effective amount to an individual or human afflictedwith said infection.
 43. A method according to claim 41, wherein saidoral pharmaceutical dosage form is administered concomitantly as twoseparate oral dosage forms, one comprising a pharmacologically effectiveamount of said acid-susceptible proton pump inhibitor or salt thereof,and the other comprising a pharmacologically effective amount of said H2receptor antagonist or salt thereof.
 44. A method according to claim 41,comprising a dose regimen capable of maintaining gastric pH above 4 forat least 95% of a time period starting at 2 hours from theadministration of the first dose and extending until 6 hours from theadministration of the last dose.
 45. A method according to claim 44,wherein said time period is at least one week.
 46. A method according toclaim 44, wherein said time period is at least two weeks.
 47. A methodaccording to claim 44, wherein said time period is at least four weeks.48. A method according to claim 41, comprising a dose regimen capable ofmaintaining gastric pH above 3 for at least 95% of a time periodstarting at 2 hours from the administration of the first dose andextending until 6 hours from the administration of the last dose, inparticular for at least four weeks.